Process for preparing 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane

Abstract

An improved process for preparing 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane comprising the selective functionalization of an acyclic tetraamine to obtain an acyclic ditosyl intermediate and an acyclic tritosyl intermediate in a first step, the independent dimerization/tosylation of the ditosyl intermediate and dimerization of the tritosyl intermediate to obtain a 1,4-phenylenebis-methylene bridged hexatosyl acyclic precursor in a second step, the cyclization of said precursor to obtain a hexatosyl cyclam dimer in a third step, and the detosylation of said cyclam dimer in a fourth step followed by basification to obtain the desired 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane.

What is claimed is: 
     
       1. A process for preparing 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane comprising the steps of: 1) selectively functionalizing an acyclic tetramine in a first step;   2) independently dimerizing/tosylating the ditosyl intermediate prepared in the first step and dimerizing the tritosyl intermediate prepared in the first step;   3) cyclizing the bridged hexatosyl acyclic precursor prepared in the second step; and   4) detosylating the hexatosyl cyclam dimer prepared in the third step and basifying to obtain the 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane.   
     
     
       2. A process according to claim 1 comprising the steps of: 1) reacting N,N'-bis(3-aminopropyl)ethylene diamine with 2 equivalents of p-toluenesulfonylchloride to obtain the acyclic ditosylate compound of formula IA and the acyclic tritosylate compound of formula IB ##STR5## 2a) in a first part a), dimerizing the ditosylate compound prepared in the first step by reacting it with 0.33 equivalents of α,α'-dibromo-p-xylene to obtain the 1,4-phenylenebis-methylene bridged tetratosyl acyclic dimer of formula IIA ##STR6## and in a second part b), tosylating the bridged tetratosyl acyclic dimer prepared in part a) by reacting it with 2 equivalents of p-toluenesulfonylchloride to obtain the 1,4-phenylene-bis-methylene bridged hexatosyl acyclic dimer of formula IIB ##STR7## 2b) dimerizing the tritosylate compound prepared in the first step by reacting it with 0.4 equivalents of α,α'-dibromo-p-xylene to obtain the hexatosyl acyclic dimer of formula IIB above;   3) cyclizing the bridged hexatosyl acyclic dimer prepared in the second part of Step 2a) and in Step 2b) by reacting it with 3 equivalents of ethyleneglycol ditosylate to obtain the hexatosyl cyclam dimer of formula III ##STR8## and 4) detosylating the hexatosyl cyclam dimer prepared in the third step and basifying the reaction mixture to obtain 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane of formula IV ##STR9##   
     
     
       3. A process according to claim 2 wherein the first step is carried out in the presence of an alkali metal hydroxide and an aromatic hydrocarbon at a temperature of from 5° C. to 40° C. for a period of between 2 and 5 hours. 
     
     
       4. A process according to claim 2 wherein the first part of Step 2a) is carried out in the presence of an alkali metal carbonate at a temperature of from 0° C. to 45° C. for a period of between 2 and 6 hours. 
     
     
       5. A process according to claim 4 wherein the first part of Step 2a) is additionally carried out in the presence of a mixture of a cyclic ether and a lower alkanol. 
     
     
       6. A process according to claim 2 wherein the second part of Step 2a) is carried out in the presence of an alkali metal carbonate and a cyclic ether at a temperature of from 15° C. to 35° C. for a period of between 1 and 4 hours. 
     
     
       7. A process according to claim 2 wherein Step 2b) is carried out in the presence of diisopropylethylamine and a cyclic ether at a temperature of from 10° C. to 45° C. for a period of between 6 and 20 hours. 
     
     
       8. A process according to claim 2 wherein the cyclization reaction of the third step is carried out in the presence of a mixture of an alkali metal hydroxide and an alkali metal carbonate and a catalytic amount of t-butylammonium sulfate. 
     
     
       9. A process according to claim 8 wherein the cyclization reaction is carried out in the presence of dimethylformamide at a temperature of from 75° C. to 125° C. for a period of between 4 and 7 hours. 
     
     
       10. A process according to claim 2 wherein the cyclization reaction of the third step is carried out in the presence of cesium carbonate. 
     
     
       11. A process according to claim 10 wherein the cyclization reaction is carried out in the presence of dimethylformamide at a temperature of from 75° C. to 125° C. for a period of between 4 and 7 hours. 
     
     
       12. A process according to claim 2 wherein the detosylation reaction of the fourth step is carried out with a mixture of hydrobromic acid and glacial acetic acid. 
     
     
       13. A process according to claim 12 wherein the detosylation reaction is carried out at reflux temperature for a period of between 30 hours and 3 days. 
     
     
       14. A process according to claim 2 wherein the basification in the fourth step is carried out with an alkali metal hydroxide. 
     
     
       15. A process for preparing 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane comprising the steps of: 1) reacting N,N'-bis(3-aminopropyl)ethylene diamine with 2 equivalents of p-toluenesulfonylchloride in the presence of an alkali metal hydroxide and an aromatic hydrocarbon at a temperature of from 5° C. to 40° C. for a period of between 2 and 5 hours to obtain the acyclic ditosylate compound of formula IA and the acyclic tritosylate compound of formula IB ##STR10## 2a) in a first part a), dimerizing the ditosylate compound prepared in the first step by reacting it with 0.33 equivalents of α,α'-dibromo-p-xylene in the presence of an alkali metal carbonate and a mixture of a cyclic ether and a lower alkanol at a temperature of from 0° C. to 45° C. for a period of between 2 and 6 hours to obtain the 1,4-phenylenebis-methylene bridged tetratosyl acyclic dimer of formula IIA ##STR11## and in a second part b), tosylating the bridged tetratosyl acyclic dimer prepared in part a) by reacting it with 2 equivalents of p-toluenesulfonylchloride in the presence of an alkali metal carbonate and a cyclic ether at a temperature of from 15° C. to 35° C. for a period of between 1 and 4 hours to obtain the 1,4-phenylenebis-methylene bridged hexatosyl acyclic dimer of formula IIB ##STR12## 2b) dimerizing the tritosylate compound prepared in the first step by reacting it with 0.4 equivalents of a α,α-dibromo-p-xylene in the presence of diisopropylethylamine and a cyclic ether at a temperature of from 10° C. to 45° C. for a period of between 6 and 20 hours to obtain the hexatosyl acyclic dimer of formula IIB above;   3) cyclizing the bridged hexatosyl acyclic dimer prepared in the second part of Step 2a) and in Step 2b) by reacting it with 3 equivalents of ethyleneglycol ditosylate in the presence of a mixture of an alkali metal hydoxide and an alkali metal carbonate, a catalytic amount of t-butylammonium sulfate, and dimethylformamide at a temperature of from 75° C. to 125° C. for a period of between 4 and 7 hours to obtain the hexatosyl cyclam dimer of formula III ##STR13## and 4) detosylating the hexatosyl cyclam dimer prepared in the third step by reacting it with a mixture of hydrobromic acid and glacial acetic acid at reflux temperature for a period of between 30 hours and 3 days, and then basifying the reaction mixture with an alkali metal hydroxide to obtain 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane of formula IV ##STR14##   
     
     
       16. A process according to claim 2 wherein the detosylation reaction of the fourth step is carried out with concentrated sulfuric acid. 
     
     
       17. A process according to claim 16 wherein the detosylation reaction is carried out at a temperature of from 80° C. to 120° C. for a period of between 2 and 5 hours. 
     
     
       18. A process according to claim 2 wherein the detosylation reaction of the fourth step is carried out with a mixture of sodium phosphate and freshly prepared sodium amalgam in an argon atmosphere. 
     
     
       19. A process according to claim 18 wherein the detosylation reaction is carried out at a temperature of from 80° C. to 120° C. for a period of between 1 and 4 days.